Cerebrum

Although a disease that has been recognized as long as written records have been kept, epilepsy is still misunderstood—even by the typical neurologist. True, most of us no longer attribute seizures to gods or demons, or use a burning goat horn for diagnosis, but our reactions to seeing a seizure often include fear, confusion, and avoidance. A neurologist who specializes in epilepsy care (an epileptologist) and is pastpresident of the American Epilepsy Society explains that seizure disorders are so diverse in their nature, causes, and treatment that even thinking of epilepsy as a single disease is a kind of myth. This confusion prevents many people with seizure disorders from getting the effectivenew treatments based on brain research.

We have all heard about some diseases, such as the common cold. We know at least a little about them, and more or less take them for granted. Other diseases we have also heard about, but we know very little about them and do not take them for granted at all. These diseases, such as leprosy and epilepsy, arouse strong emotions—fear and confusion, even a desire to reject the people who suffer from the disease. People with leprosy become disﬁgured and look frightening; the disease is contagious. To the uninformed observer, leprosy offers a lifetime sentence of social isolation. Naturally, people are frightened of catching it and may shun those with the disease. But why epilepsy?

People with seizures look like everyone else when they are not having a seizure, and seizures are not contagious. Yet, as far back in history as we know, people with seizure disorders have been viewed with fear. In many civilizations, they have been shunned; in others, they have been thought to have a special ability and be in communication with higher powers—good gods in the case of the Romans, the devil in the case of early Christianity. The early Greeks called epilepsy “the sacred disease,” but it later became known as “the scourge of Christ,” probably as a result of the passage in the Gospels in which Jesus casts out an unclean spirit from a young boy. The boy’s father says (in the Gospel according to Luke), “Teacher, I implore you, look on my son...Behold, a spirit seizes him, and he suddenly cries out; it confuses him so that he foams at the mouth; and it departs from him with great difﬁculty, bruising him.” To this day, many ordinary people still believe patients with epileptic seizures are “possessed,” and a person with seizures is forbidden to take Holy Orders (become a priest) in the Roman Catholic Church.

Many people have a rather ﬁxed image of what a seizure looks like. Consider this passage from The Idiot, by Fyodor Dostoevsky (who himself suffered from epileptic seizures). The hero, Prince Myshkin, is about to be attacked by a man with a knife:

"Then all at once everything seemed to open up before him: an extraordinary inner light ﬂooded his soul. That instant lasted, perhaps, half a second, yet he clearly and consciously remembered the beginning, the ﬁrst sound of a dreadful scream which burst from his chest of its own accord and which no effort of his could have suppressed. Then consciousness was extinguished instantly and total darkness came upon him. He had suffered an epileptic ﬁt, the ﬁrst for a very long time. As is well known, attacks of epilepsy, the notorious falling sickness, occur instantaneously. In that one instant the face suddenly becomes horribly contorted, especially the eyes. Spasms and convulsions rack the entire body and all the facial features. A frightful, unimaginable scream, quite unlike anything else, bursts from the chest. "

Study the faces of bystanders when someone has a seizure similar to Prince Myshkin’s. It is not difﬁcult to imagine what might be going on in their thoughts. The situation appears strange, even frightening. The person having the seizure is out of control—what is worse, out of our control. We do not know how to respond. In fact, his seizure saves Prince Myshkin’s life. Unnerved by the sight, his attacker ﬂees.

Yet everyone can have a seizure, and many seizures are neither epileptic nor nearly as dramatic as the one portrayed by Dostoevsky. Seizures are part of the normal repertoire of responses of the human brain. Some people, more than you might think, have seizures spontaneously, without any apparent immediate trigger. One of every eleven people has a seizure sometime in his life.

What, then, is this mysterious condition called epilepsy? Is it a speciﬁc disease? Scientists have now made great progress in understanding what takes place in the brain when a seizure occurs and which brain circuits are perturbed in such a way that a seizure is produced. They are also beginning to unravel the connections between the appearance of a seizure, these circuits, and what we commonly talk about as “causes,” for example, tumors, brain trauma, and strokes. On the basis of these discoveries, there are increasing possibilities for controlling and treating epilepsy, and eventually even for curing or preventing it. But seizure disorders are a complicated problem for which there is no simple solution, and, for a variety of economic and social reasons, many patients with epilepsy are not receiving even the current best available care.

WHAT IS A SEIZURE?

To fully deﬁne a seizure in modern scientiﬁc terms, we must analyze it at the levels of behavior, physiology, chemistry, and genetics. People display a broad variety of behaviors during a seizure. Characteristically, the seizure starts suddenly, usually lasts for a brief period of time, and ends abruptly. The behavior can include anything from an almost unobservable loss of focus to the kinds of dramatic actions described by Dostoevsky—screaming, falling, convulsing. Afterward, the person can be tired or confused. But this description on the behavioral level is too simple to deﬁne a seizure. Many literary conventions make that obvious; people “stop dead in their tracks” or are “struck dumb,” for example.

A more complete and scientiﬁcally sophisticated deﬁnition can be found in the textbook, Comprehensive Neurology, edited by Roger Rosenberg, M.D.:

"A seizure can be deﬁned as a sudden, involuntary, time-limited alteration in behavior involving a change in motor activity or autonomic function, a change in consciousness, or a change in sensation, accompanied by an abnormal electrical discharge in the brain. Epilepsy is not a single disease. Seizures are symptoms of a disturbance in brain function that may have many different causes and cannot be treated properly without understanding the underlying disturbance or disease process."

Note that this deﬁnition includes a change in the brain’s neurophysiologic state, which must be observed by looking at changes in the electrical activity of the brain recorded by an electroencephalogram (EEG). Because seizures are episodic, they cannot be seen just because the doctor chooses to look at the brain at some particular time. Seizures are, therefore, hard to diagnose and consequently hard to treat. This difﬁculty in observing seizures is just one of the many unfortunate reasons why many people have uncontrolled seizures for years.

FROM SINGLE EVENT TO IDENTIFIABLE DISORDER

If a seizure is a single event, what is a seizure disorder? The modern medical taxonomy tries to classify problems as speciﬁc diseases or disorders. A disease is something that has a common cause—a common etiologic agent, or at least a group of similar etiologic agents. Furthermore, a disease should display a relatively uniform pathophysiology, and most people with it should respond to similar treatments. Unfortunately, this does not hold true for epilepsy.

Seizures have many causes, many different manifestations, and many different treatments. In fact, in modern scientiﬁc parlance, epilepsy means only that someone has had more than one seizure on more than one occasion. But epilepsy syndromes are another matter. At the broadest level, seizure disorders can be divided into two primary groups: nonepileptic seizure disorders, in which something in the body or mind affects the behavior of otherwise normal neurons and brain circuits, and epileptic seizure disorders, which are caused by intrinsic neuronal or brain circuit malfunction. The chart that follows provides a broad outline of how these two groups are deﬁned and subdivided.

We can look at nonepileptic seizure disorders as falling into two main groups. In the ﬁrst subgroup, the cause of the seizures is an identiﬁable physiologic problem, such as a cardiac or respiratory problem or a toxin. One common and striking example is Stokes-Adams disease. The heart of a patient with Stokes-Adams disease suddenly stops beating. If the pause is long enough, the brain suffers a lack of oxygen (carried by the hemoglobin in the blood), and a seizure results. Even though the EEG shows seizure activity, the primary problem here is not with the physiology of the brain but with the inadequate oxygen that it receives.

In the second subgroup of nonepileptic seizure disorders, the cause appears to be psychogenic. This subgroup consists of patients whose behavior resembles an epileptic seizure, but in whom (among other things) no disturbance in the EEG can be identiﬁed during a seizure. This fascinating group of people has serious psychological and social problems, consumes a large amount of medical resources, but can respond well to psychological treatment. Unfortunately, what are called “psychogenic nonepileptic events” are poorly understood by most physicians (and most health insurance companies). Patients with psychogenic events have great difﬁculty getting access to competent treatment.

THE MANY KINDS OF EPILEPTIC DISORDERS

As with nonepileptic seizure disorders, we can further divide the large group of epileptic seizure disorders. To be useful, any classiﬁcation should help the physician decide on the type of treatment and give the patient some idea of what is likely to happen to him in the future. Before the 1960s, physicians talked about grand mal and petit mal seizures—big ones and little ones. This very crude classiﬁcation was scientiﬁcally meaningless, but it did help identify those patients (the ones with grand mal seizures) who were at most risk of respiratory distress and sudden death.

In the past 50 years, however, an international consensus has been reached that epileptic seizures should be classiﬁed by specifying which part of the brain is involved in initiating them. This classiﬁcation has proved to be useful, although recent genetic studies are likely to lead to a new classiﬁcation. Currently, epileptic seizures are divided into two broad classes: primary generalized and localization-related.

Primary generalized seizures appear to begin instantaneously throughout the brain, affecting the entire brain at the same time, although there is now some evidence to suggest that there actually could be a beginning locus and an extremely rapid spread. From the standpoint of managing patients and directing research, however, the classiﬁcation is still useful. Many different epileptic syndromes can be considered in the category of primary generalized seizures. The three most common groups are:

Absence seizures of childhood, which manifest as a brief blank stare and sometimes rapid blinking or chewing motions. The child is unaware of what goes on during the seizure but quickly returns to full awareness.

Primary generalized seizures in children and young adults include generalized tonic-clonic seizures—the type previously known as grand mal and which some call a convulsion. Generalized tonic-clonic seizures begin with stiffening of limbs (the tonic phase), followed by jerking of the limbs and face (the clonic phase). They can be accompanied by changes in breathing or incontinence and are followed by a period, lasting from minutes to hours, of lethargy, confusion, headache, or wanting to sleep.

Primary generalized seizures with a strong myoclonic component (juvenile myoclonic epilepsy) include brief, massive muscle jerks that can involve the whole body or parts of the body and cause a person, for example, to spill what he was holding or fall off a chair.

The largest and most fascinating group of epileptic seizure disorders, at least from the point of view of understanding brain function, is what are called localization-related, or partial, epilepsies. A seizure that begins in a small part of the brain and stays localized is called a partial seizure; if it involves a large enough portion of the brain that consciousness is also affected to some degree, it is called a complex partial seizure.

In addition to primary generalized seizures and localization-related seizures, a third group can be considered a combination of the two. In secondarily generalized seizures, an initially partial seizure spreads to involve the entire brain.

UNRAVELING THE CAUSES

With so many complex categories of epileptic and nonepileptic seizure disorders, you would be right to assume that the causes are equally diverse and complex. There are three primary groups of causes: the aptly named cryptogenic (that is, unknown), primary (intrinsic to the brain, often genetic), and secondary, caused by observable injury to or malformation of the brain. What is more, certain causes of seizures tend to produce certain kinds of seizures.

For example, a patient who has a primary generalized tonic-clonic seizure is much more likely than other patients with seizures to be suffering from a genetic, metabolic, or toxic disorder caused by something such as lack of adequate blood glucose, alcohol withdrawal, or substances such as amphetamines, ephedrine, or cocaine.

Historically, primary generalized seizures were thought to be more likely than localization-related seizures to be inherited. Now, we know that even seizures that begin in one part of the brain can have a strong genetic component.

Historically, primary generalized seizures were thought to be more likely than localization-related seizures to be inherited. Now, we know that even seizures that begin in one part of the brain can have a strong genetic component.

The most easily recognized causes of secondary localization-related seizures are injuries such as skull fractures caused by motorcycle, bicycle, and automobile accidents; bullet and shrapnel wounds; strokes; and brain tumors. Meningitis and encephalitis, which can lead to seizures, are still not always avoidable.

One cause of seizures that can now be identiﬁed are genetic migration disorders. When the brain is constructed in the womb, nerve cells are formed in the center part of the brain and migrate out to form the cortex. If something goes wrong in this process, a collection of cells can end up in the wrong spot. These abnormally connected neurons can serve as a potent provocative agent for seizures.

An important cause of seizures that far too few physicians have learned to recognize is what is called mesiotemporal sclerosis. In a young child, high fever of almost any origin, particularly if associated with a prolonged seizure, can damage the brain’s hippocampus. After a few years of relatively good health, without seizures, the child may begin to experience complex partial seizures produced by the injured hippocampus.

STUDYING SEIZURES

We have come a long way from ancient attempts to diagnosis seizures. In the Roman era, it was the practice to give someone suspected of having epilepsy a piece of the black mineral, jet, to smell. If the person did not fall to the ground, he was considered free of “the falling sickness.” To produce the same kind of test, the Greek physician Alexandros of Tralleis (525-605) suggested “Wash the head of the patient and burn a goat’s horn under his nose and he will fall down.” Modern researchers and physicians use a combination of behavioral analysis and EEG recordings of the brain, not just for diagnosis but also to study the functions of different parts of the brain. Patients are admitted to the hospital, and any antiepileptic medications they were taking are withheld. They are then videotaped during any seizure that results, and simultaneously an EEG recording is made. Their brains can also be studied through a variety of modern neuroimaging techniques.

What kind of activity, or behavior, occurs during a seizure is connected with the localization of various functions in the brain. Limb movements come from the neocortex, anxiety attacks come from the right temporal lobe, disturbance of speech comes from Broca’s area in the left frontal lobe, and laughing seizures come from lesions in the ventral part of the hypothalamus, to name just a few examples. To experience a disturbance of consciousness seems to require bilateral involvement of the frontoparietal lobes. Without both sides being involved, consciousness is not lost but can be somewhat impaired.

EXCITING AND INHIBITING THE ACTIVITY OF NEURONS

Scientists are now able to observe the electrical activity taking place in the multilayered areas of the cerebral cortex where epileptic seizures are generated. When excitatory inﬂuences overwhelm the inhibitory inﬂuences, the excitation spreads, and a seizure results. How does this occur?

In most cases, information is transferred from one neuron to another synaptically, that is, by the passage of a chemical from the axon of one neuron to the dendrites or the soma (main body) of another. These chemicals can either excite or inhibit the activity of the receptor neuron. In all living neurons, there is a difference in electrical potential between the inside of the cell and the outside of the cell; this difference, measured in volts, is called the membrane potential. This voltage is maintained by the difference in the concentration of ions, primarily sodium, potassium, and chloride, between the two sides of the membrane. If something affects a neuron to reduce the potential difference and if this depolarization is strong enough, what is called an action potential will be generated. Action potentials are an all-or-none phenomenon. They are the ﬁnal common expression of the inhibitory and excitatory inﬂuences on the neuron. Multiple, complex factors are involved in changing excitability in neuronal circuits, and different kinds of synaptic transmitters have different effects.

THE GENETICS OF EPILEPSY

An analysis of the many neurotransmitters and their receptors opens the way to understanding the genetics of epilepsy. For example, there is an epileptic syndrome called generalized epilepsy with febrile seizures plus (GEFS+). Patients with GEFS+ typically have seizures with high fevers before the age of three months or after three years of age. In addition, they can have any other kind of seizure, even in the absence of fever. A single mutant gene was found in a large group of GEFS+ patients that affects a particular voltage-gated sodium channel, changing the excitability of the neurons so that this very speciﬁc seizure syndrome can result.

But if all these patients have the same single mutation, why can they have so many different kinds of seizures, in addition to the febrile seizures they all have in common? The answer is that people have all kinds of genes and, depending on the rest of their genetic make-up, one or another type of additional seizure may be more or less likely to occur.

FURTHER AREAS OF EXPLORATION

Scientists have searched for autoimmune causes of epilepsy for years. Recent studies of the seizures associated with Rasmussen’s encephalitis suggest that an antibody against a particular glutamate receptor plays a role, but researchers are still working to understand this phenomenon.

Another process being investigated is axonal sprouting after injury, particularly in the brain’s hippocampus. It is still not clear whether the synapses formed by these new neuronal axons actually excite other cells in the hippocampus. What is clear is that even in adults it is possible for new cells to form in the hippocampus after injury and that these new cells may not hook up in a normal fashion within the brain. That is, they may not connect with the same neurons in the same way as occurs during the development of the normal fetus. These abnormal connections may be a cause of seizures.

A similarly exciting new area of investigation is the study of seizures associated with what are called heterotopias, or migration disorders. In the developing fetus and infant, normal brain cells migrate from the center of the brain toward the cortex. If something goes wrong, malformations, abnormalities in the location of the cells, dysplasias, and other disturbances in the structure of the cerebral cortex can occur. Recent research suggests that these misplaced neurons have a problem with a particular potassium channel that could produce hyperexcitability, while other research suggests that there could be impaired inhibition.

TREATING EPILEPTIC SEIZURE DISORDERS

Ancient Greeks believed a person got epilepsy by offending the moon goddess Selene; one purported cure was eating mistletoe that was picked without a sickle or blade during the time the moon is smallest in the sky. The mistletoe, which grows clinging to the high branches of trees, could not be allowed to fall on the ground because then it would not be effective against the falling sickness. Modern treatments, both pharmaceutical and surgical, are considerably more effective.

The primary treatment for seizures is prescription of antiepileptic drugs (AEDs). Before scientists understood the mechanisms underlying epileptic seizures, the search for such drugs was by trial and error, testing many compounds on experimental animal models and hoping for a happy accident. Only recently have we begun to learn how drugs used for many years actually work. The most common mechanism of action of AEDs is to affect voltage-sensitive ion channels, especially sodium, potassium, and chloride channels. New drugs developed based on this understanding, for example gabapentin and tiagabine, have not been very powerful, but understanding the ions involved in the synaptic regulation of excitability offers hope for designing better AEDs.

The physiologic analysis of how seizures spread in the brain has led to corrective surgery to cure epilepsy. Complex partial seizures of temporal lobe origin can be effectively cured in most appropriate cases by an operation called an anterior temporal lobectomy. Furthermore, the anatomical approach (surgery), the chemical approach (voltage gated channels), and genetics are now beginning to intersect. For example, patients with antiepileptic drug resistance may be more likely to have a particular genotype, although this may not be the cause per se but merely linked with the causal variation. In other words, we can identify this gene, but it may not be the active one—it just goes along.

Epileptologists are learning to match different types of AEDs with their effects on different kinds of seizures and link certain kinds of treatments to speciﬁc epilepsy syndromes, greatly improving the success of therapy. One of the major clinical debates of the moment is how early to perform an anterior temporal lobectomy, rather than continuing to try for pharmaceutical control. The likelihood of a patient having complete seizure control after failing two major antiepileptic medications is less than ﬁve percent. And expert medical treatment in cases of refractory temporal lobe epilepsy yields only a small improvement in seizure control, but 70 percent of patients are cured by an anterior temporal lobectomy.

CHALLENGES IN ACCESSING TREATMENT

Sadly, all of this knowledge about the many kinds of seizures, their causes, and increasingly effective treatments is not helping most people with epilepsy. Many patients still have seizures, and even patients with good health insurance may fail to beneﬁt from the best that modern treatment can provide. Effectively treating seizures in patients who do not respond promptly to standard doses of ordinary medicine usually requires seeking out a major epilepsy center, which brings together the efforts of epileptologists, neuropsychologists, psychologists, pharmacists, and neurosurgeons in an interdisciplinary approach. But these centers commonly report that it takes about 15 years before a patient with uncontrolled seizures ﬁnally reaches them, whether on the patient’s own initiative or referred by a physician. This is obviously a major public health issue, and conferences sponsored by the Centers for Disease Control and Prevention have recommended that patients whose seizures have not been brought under complete control after only 3 to 12 months of treatment should be immediately referred to an epilepsy center.

Epilepsy is a relatively low-frequency disorder. In the United States, almost 200,000 new cases of epilepsy are diagnosed each year, and approximately 2.5 million people are considered as having active epilepsy, as deﬁned by a history of the disorder plus a seizure or use of antiepileptic medication within the past ﬁve years. Although those numbers may sound large, what they mean in practice is that the average family doctor will see only one patient with epilepsy every other year and treat ﬁve or six patients with epilepsy in his practice. The average neurologist may follow 25 to 50 patients. This is simply not enough of a concentration of patients to justify devoting the time and energy necessary to keep up to date with the latest discoveries and to understand such a complex disorder. Adding to the problem are increasing restrictions by health maintenance and preferred provider organizations on referring patients to out-of-network specialists.

We must also consider the effect of the social environment on the person with epilepsy. Because one cannot always predict a seizure, it can happen unexpectedly at any time, in any place. Waking up on the ground surrounded by a group of gawking bystanders convinces many patients with epilepsy to stop going out in public, and they become socially isolated. In today’s modern, high-tech culture, having a seizure disorder is much more of a burden than it was in simpler times. People with insufﬁciently controlled seizure disorders are not permitted to drive and face many obstacles to employment. Not having a job is very hard on one’s self-esteem, and in the United States today, health insurance usually comes from one’s employer. If someone with epilepsy is unemployed, no one will sell him health insurance. If a person is poor, she may be able to get some, but not necessarily adequate, help from the federal and local governments.

Lack of adequate care when a seizure disorder is ﬁrst diagnosed carries an additional danger. What is not widely understood is that epilepsy can be a progressive disorder. Seizures beget seizures and produce progressive difﬁculty with memory. As the seizures get worse and the physician increases the amount of antiepileptic medication, the side effects further interfere with brain function.

How can we avoid this downward spiral? Early and effective treatment is essential, as are efforts to avoid situations that can produce the brain damage that causes seizures in the ﬁrst place.

How can we avoid this downward spiral? Early and effective treatment is essential, as are efforts to avoid situations that can produce the brain damage that causes seizures in the ﬁrst place. Many Western European governments have set up triage networks through which patients with seizures go immediately to epilepsy experts, rather than being treated by a physician who is not specially trained. Unfortunately, the health care system in the United States does not make it easy for a patient to be managed by a family doctor with the help of an epilepsy expert. Patients with seizure disorders and their families have to advocate for themselves if they are going to get the help they need.

People with epilepsy have long been misunderstood, even feared and shunned. But they are afﬂicted neither by gods nor demons but by misﬁring brains. We now understand just how complex epilepsy is, how many kinds and causes of seizures exist, each requiring different kinds of treatments. The choices are myriad and require management by experts. One size no longer ﬁts all.

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About Cerebrum

Bill Glovin, editor Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board Joseph T. Coyle, M.D., Harvard Medical School Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital Robert Malenka, M.D., Ph.D., Stanford University School of Medicine Bruce S. McEwen, Ph.D., The Rockefeller University Donald Price, M.D., The Johns Hopkins University School of Medicine